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Theobromine as a molecular switch: targeting Nrf2 pathway in invasive and non-invasive bladder cancer
Beyza Ecem Oz-Bedir1,2, Elif Ercan3,4, Emine Terzi3,4
1Department of Medical Biology, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Türkiye. beyzaecemozbedir@aybu.edu.tr.
Abstract:
Naturally occurring compounds like Theobromine, found in tea, coffee, and cocoa, may have anticancer effects. This study explores how Theobromine induces cell death and apoptosis in bladder cancer cells and its impact on NRF2-related gene activity. Two human bladder cancer cell lines-RT112 (non-invasive) and HTB9 (invasive)-were employed. Cell viability was measured using the WST-1 assay, whereas apoptosis and caspase 3/7 activation were determined through flow cytometry. qPCR was performed to measure the expression of NRF2, KEAP1, and P62 genes. Theobromine exhibited a dose-dependent reduction in cell viability in both RT112 and HTB9 bladder cancer cells, while also significantly enhancing apoptosis and caspase 3/7 activity (p<0.0001). Flow cytometry analysis indicated G1-phase arrest in RT112 cells and S-phase accumulation in HTB9 cells following Theobromine treatment, while Cisplatin induced S-phase arrest in both cell lines. Theobromine suppressed NRF2 and P62 while increasing KEAP1 levels in HTB9 cells, suggesting NRF2 pathway inhibition. For RT112 cells, Theobromine upregulated NRF2 and P62 without altering KEAP1 expression, highlighting cell type-specific modulation of the NRF2 signaling pathway. This study shows that Theobromine differentially regulates the Nrf2-Keap1-p62 pathway in bladder cancer cells, inhibiting NRF2 and P62 expression in a cell-specific manner. These findings suggest its potential as a natural anticancer compound, warranting further in vivo studies to assess its therapeutic potential.
Insights
Theobromine, a natural compound, effectively reduces bladder cancer cell viability and induces apoptosis. It also impacts the NRF2 pathway differently in invasive and non-invasive cancer cells, showing potential as an anticancer agent.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Theobromine, a natural compound from cocoa, tea, and coffee, is investigated for potential anticancer properties.
- Bladder cancer remains a significant health concern, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the effects of Theobromine on bladder cancer cell death, apoptosis, and cell cycle progression.
- To explore Theobromine's impact on the NRF2-KEAP1-P62 signaling pathway in different bladder cancer cell lines.
Main Methods:
- Utilized two human bladder cancer cell lines (RT112 and HTB9) for in vitro experiments.
- Assessed cell viability using WST-1 assay, apoptosis and caspase 3/7 activity via flow cytometry.
- Quantified gene expression of NRF2, KEAP1, and P62 using qPCR.
Main Results:
- Theobromine demonstrated a dose-dependent decrease in bladder cancer cell viability and significantly increased apoptosis and caspase 3/7 activity (p<0.0001).
- Cell cycle analysis revealed G1-phase arrest in RT112 cells and S-phase accumulation in HTB9 cells.
- Theobromine modulated the NRF2 pathway in a cell-specific manner, suppressing NRF2/P62 and increasing KEAP1 in HTB9 cells, while upregulating NRF2/P62 in RT112 cells.
Conclusions:
- Theobromine exhibits potent anticancer effects by inducing apoptosis and altering cell cycle progression in bladder cancer cells.
- The compound differentially regulates the Nrf2-Keap1-p62 pathway, suggesting cell-specific mechanisms of action.
- Theobromine shows promise as a natural anticancer agent, meriting further in vivo investigation for therapeutic potential.
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